Aneuploidy, the state of having uneven and abnormal chromosome copy numbers, is a frequently observed genome variation in eukaryotes and is a hallmark of cancer thought to play important roles in cancer evolution and development of drug resistance. The goal of this project is to use a creative combination of cell biology, genetics and genomic analyses in the model organism, the budding yeast Saccharomyces cerevisiae, to gain fundamental insights into how aneuploidy affects genome stability, cellular physiology and stress adaptation. We have recently developed several new methods to generate isogenic aneuploid yeast strains with random chromosome stoichiometry and to follow karyotype dynamics in aneuploid populations. These methods have allowed us to make important observations on the relationship between aneuploidy and cellular stress, and the profound impact of chromosome copy number variation on gene expression and fitness. The proposed study builds upon these findings with four specific aims. The first aim attempts to further understand the consequence of aneuploidy on gene expression by investigating its potential effects on epigenetic regulatory mechanisms. The second aim focuses on the question of why aneuploidy has a tendency to promote further chromosome instability leading to karyotypically mosaic populations adaptive to a wide range perturbation. The third aim investigates the possible existence of a common stress state associated with aneuploidy. The last aim explores a strategy of exploiting aneuploidy and karyotype dynamics, which may be potentially useful for treating cancer or fungal infections.